The advantages of few seconds duration all filed simultaneous radiation therapy (AFSRT) with super high combined dose rate at isocenter is described in above cross-referenced non-provisional and provisional patent applications and disclosure. The AFSRT overcomes the disadvantages associated with lower daily radiation dose.
The isocentric super high dose rate of all field simultaneous radiation therapy (AFSRT) is the combined dose rate of all converging simultaneous beams at the isocenter (1). Its (3D2 cell kill is much higher than in conventional radiation therapy that is delivered by subfractionated daily-fractionated radiation therapy. Here, the daily subfractionated radiation therapy is referred to as the daily-fractionated radiation therapy that is further subfractionated by treating each field sequentially. Such daily fractionated treatment is interrupted by the time required for sequential setup of treatment fields and then switching the beam on for the treatment. When a tumor at isocenter is treated by the method of AFSRT, the Dmax dose to normal tissue depends on the number of simultaneous beams; as described below, it is very much reduced.
The production of monochromatic, high-flux, short-pulse x-rays with the interaction of electron beam and laser photon beam uses high energy electron beam, in the range of about 25-44 and higher MeV. After the electron-laser photon beam interaction, the high energy electron beam is dumped as a waste product (2, 3). The electron beam source can be from a conventional linear accelerator (2), a superconducting linear accelerator (3) or any other high energy electron beam generating accelerators like the Betatron, Microtron, Racetrack Microtron or any other high energy electron beam generators. In this invention, such high energy electron beam is used for direct electron/photon beam radiation therapy. The monochromatic x-ray pulse generated by the interaction of electron and laser photon beams is used for imaging combined with radiation therapy and tumor specific radiation.
Electron Beam Radiation Therapy
External beam radiation therapy is mostly delivered by high energy photon beam. An alternative method of radiation therapy with high energy electron would eliminate the about 45% exit dose contribution from the parallel opposing beam to the skin as in radiation therapy with photon beam. The electron beam do not generate contaminating direct neutron beam or by its interaction with a patient as by the photon beam. The contaminating x-ray beam of the high energy electron beam could reach the opposite side of a treatment field but it is generally very low as compared to the photon beam's exit dose. Furthermore, the filtered contaminating x-ray at the tail end of the electron beam is superior to the monochromatic filtered low energy x-rays that are also used for phase contrast imaging. The 90 and 80% of the electron beam is approximately E/3.2 and E/2.8. Hence the 30 MeV electron beam's useful treatment depth at 90 and 80% is about 10 and 12.5 cm. It is a sufficient depth dose for routine radiation therapy. Taking the loss of electron energy at a rate of about 2 MeV/cm of water or soft tissue, the 30 MeV electron beam's range is about 15 cm. Hence the 30 MeV electron beam's dose contribution to the opposite side of an average person with 20 cm circumference is negligent except for its small amount of x-ray contamination.
Inverse Compton Scattering (ICS), Monochromatic X-Ray Imaging
Interaction of electron beam with laser beam is used to generate short pulse monoenergetic x-ray beam (2, 3). Such inverse Compton scattering monoenergetic x-ray offers numerous advantages to study the biological events that takes place immediately after radiation. It offers the opportunity to facilitate monochromatic x-ray image guided radiation therapy. In phase contrast imaging of tissue with short pulse monoenergetic x-rays, the perturbaration of x-rays by the component of the cellular elements is visualized. When imaging is by bremsstrahlung x-rays, the x-ray is absorbed by the tissue. The phase contrast imaging minimizes the x-ray dose to tissue than the conventional methods of imaging with bremsstrahlung x-rays. It is also suited for phase contrast imaging during and or immediately after radiation therapy. The few seconds duration all field simultaneous radiation therapy with isocentric super high dose rate and tumor specific k-edge radiation will cause much more DNA damage and molecular level reactions. The combined radiation therapy and molecular imaging by phase contrast is an entirely newer method of radiation therapy of cancer. It offers unsurpassed opportunities like in vivo imaging of protein constituents in tissue that is radiated with super high dose rate radiation. It allows to investigate the radiated tissue's magnetic scattering, time dependent radiation induced −OH ion migration to DNA and DNA double strand breaks, the effects of hyperthermia combined with radiation therapy and formation of receptor-ligand complexes in tumor tissue like that of hormones and chemotherapeutic agents. It also offers many other investigational opportunities including spectroscopic analysis of structural differences in proteins in normal and tumor cells as well as the structural genomics of the normal and cancer cells. They would help to correlate and predict the outcome of a treatment modality at molecular level, especially of the potential tumor cure, recurrence and metastasis.
Recently, less expensive, compact monochromatic high brilliance x-ray production sources are described (2, 3). In such high brilliance x-ray source generation, high energy electron is made to interact with laser photon beam. This electron-laser interaction generates inverse Compton x-ray which is used for phase contrast imaging.
Inverse Compton scattering X-Ray's Electron Beam for Radiation Therapy
In inverse Compton scattering x-ray generation as in U.S. Pat. No. 6,687,333 B2 by Carroll F. E et al (2), in U.S. Pat. No. 7,391,850 by Kaertner et al (3) and in U.S. Pat. No. 7,027,553 by Dunham B. M (22), after the electron—laser interaction, the spent high energy electron beam is “dumped” away as a waste product. In this invention, instead of dumping this spent electron beam, it is reused for either electron beam radiation therapy or for photon beam radiation therapy. Alternatively, after the monochromatic x-ray imaging, separate electron beams suitable for radiation therapy is generated in the accelerator unit that is used to generate the electron beam. By varying the wave length of the laser or the energy of the electron beam, different energy, tunable monochromatic x-ray is obtained.
For all field simultaneous radiation therapy, the spent electron beam of the inverse Compton reaction is deflected into circular beam lines that are equipped with multiple treatment heads. The electron beam energy used for generating monochromatic, high pulse x-ray ranges from 25-44 MeV and higher (2,3, and 22). This electron beam is used for high energy electron beam radiation or to generate high energy photon beam for photon beam radiation. Alternatively, separate lower energy electron beam is generated in the accelerator for lower energy radiation therapy. In this instance the electron accelerator operates in multiple energy modes. The high flux short pulse monochromatic x-rays generated by the interaction of electron beam and the laser beam is deflected for phase contrast imaging and the electron beam that is deflected into the beam line is used for radiation therapy.
All Field Simultaneous Radiation Therapy Combined with Monochromatic X-Ray Imaging
The method of generating monochromatic high flux, short pulse x-ray beam is described in U.S. Pat. No. 6,687,333 B2 by Carroll F. E et al (2), in U.S. Pat. No. 7,391,850 by Kaertner et al (3) and in U.S. Pat. No. 7,027,553 by Dunham B. M (22). The high flux, short wave x-ray is deflected into a collimated imaging system for imaging. Imaging with monochromatic x-ray renders 100-100 times superior image quality with much less radiation to the target tissue (2). The electron is deflected into a beam line for all field simultaneous radiation therapy. It offers simultaneous imaging while radiation therapy is rendered. Alternatively, after the phase contrast imaging the high energy electron beam is dumped as a waste and for radiation therapy, lower energy, say 6 or 10 MeV is generated in the accelerator as separate beam and deflected into the beam line for radiation therapy. After or even during the radiation therapy, phase contrast imaging is used to analyze radiation induced reactions in the cell. It allows imaging of cellular level events during or after radiation. Such elaborate image guided radiation therapy is not feasible with present image guided radiation therapy.
The electron beam that is deflected into the beam line is split into two at each station where a treatment head is located. One of such split beam is bent towards treatment head. The other beam is bent towards the next treatment head where it is spit into two again, one is bent towards the next treatment head and the other is deflected towards the next treatment head. This process of splitting the beam and bending one beam towards a treatment head and another beam towards the next station where the next treatment head is located is repeated until all the simultaneous beams are generated for all filed simultaneous radiation therapy.
Few Seconds Beam on Time All Field Simultaneous Radiation Therapy
The beam on time for all field simultaneous radiation therapy with multiple simultaneous beams is very short. The beam on time is 40 seconds if it were a four field simultaneous radio surgical dose were 800 cGy. This beam on time is progressively decreased as the number of simultaneous beams are increased; if it were a 8, 16 or 32 simultaneous beams system, then the beam on time to deliver 800 cGy will be decreased to 20, 10 and 5 seconds respectively. Because of this system's super high dose rate associated improved RBE, the single dose of 800 cGy might be equivalent to about 1,000 cGy or higher. A patient can be instructed to hold breathing for 5-20 seconds. It enables breathing synchronized radiosurgery. If it were a medical accelerator system with four simultaneous beams, the beam on time to deliver 800 cGy single doses would be 40 seconds. It is a longer time for a patient to hold the breathing. In this instance, breathing synchronized two fractions of 400 cGy are delivered, each fraction's beam on time lasting 20 seconds. The beam on time for conventional 200 cGy daily fractionated radiation therapy is 5 seconds. It is rendered as breathing synchronized radiation therapy.
If the single beams dose rate were 200 cGy and isocentric depth 10 cm below the skin and if the average TMR were 0.746, Sc 0.98, Sp 0.99 then the Diso=D0 200 cGy×0.746×0.98×0.99 which is 144.8 cGy. (29). Likewise, if the single beams dose rate were increased to 400 cGy and isocentric depth 10 cm below the skin and if the average TMR, Sc and Sp were same as above, then the Diso=D0 400 cGy×0.746×0.98×0.99 which is 289.5 cGy. If the number of simultaneous beams were 2, 4, 8, 16 or 32, then the isocentric additive (biological dose rates) for this AFSRT system is 2×289.5=579 cGy/min, 4×289.5=1,158 cGy/min, 8×289.5=2,316 cGy/min, 16×289.5=4,632 cGy/min and 32×289.5=9,264 cGy/min (1). If 800 cGy Diso were given by 2, 4, 8, 16 or 32 simultaneous beams and each beams having 400 cGy/min dose rates, then each beams delivers 400, 200, 100, 50 or 25 cGy at the isocenter. It is proportional to the isocentric dose 800 cGy divided by the number of beams. Alternatively it can be calculated by dividing each beam's contribution divided by each beam's Diso dose rate of 289.5 cGy. If there are two simultaneous beams, then the treatment time to deliver 800 cGy at the isocenter is (800/2)/289.5, which is 1.3817 min or 82.9 seconds. In this instance, the MU set up for each beam is D0 dose rate per min 400×1.3817, which is 552.677, or 553. Likewise, if there are four simultaneous beams, then the treatment time is reduced to (800/4)/289.5, which is 0.6908 min or 41.45 seconds. In this instance, the MU set up for each beam is D0 dose rate per min 400×0.6908, which is 276. Similarly, if it were eight simultaneous beams, then the treatment time is reduced to (800/8)/289.5, which is 0.3454 min or 20.7254 seconds. In this instance, the MU set up for each beam is machine dose rate per min 400×0.3454, which is 138. Likewise, if it were sixteen simultaneous beams, then the treatment time is reduced to (800/16)/289.5, which is 0.1727 min or 10.362 seconds. In this instance, the MU set up for each beam is machine dose rate per min 400×0.1727, which is 69. Similarly, if it were 32 simultaneous beams, then the treatment time is reduced to (800/32)/279, which is 0.0864 min or 5.1813 seconds. In this instance, the MU set up for each beam is machine dose rate per min 400×0.0.0896, which is 34.54. By increasing the number of beams from different angles, the D0 dose is decreased while the isocentric additive dose rate is maintained as the same. The decrease in individual beam's dose contribution at the isocenter is proportional to the number of simultaneous beams.
Alternatively, individual beam's beam on time can be calculated from the isocentric total dose Diso-T divided by total additive D0 dose rate, D0-T. The MU setup for each of the simultaneous beam is then each individual beam's dose rate D0 x beam on time. If the individual beam's dose rate were 400 cGy/min and the treatment parameters the same as above, then the individual beam's Diso dose rate is 289.5 cGy/min. The tumor dose is kept as the same before, 800 cGy. If the number of simultaneous beams were 2, 4, 8, 16 or 32, then the total additive dose rates, D0-T are 400×2=800, 400×4=1,600, 400×8=3,200, 400×16=6,400 and 400×31=12,800 cGy. These 2, 4, 8, 16 or 32 simultaneous beams's total additive dose rate Diso-T (biological dose rates) is 2×289.5=579, 4×289.5=1,158, 8×289.5=2,316, 16×289.5=4,632 and 32×289.5=9,264 cGy/min. Then the beam on time to deliver 800 cGy at the isocenter for 2, 4, 8, 16 or 32 simultaneous beams is 800/579, 1,158, 2,316, 4,632 or 9,264 cGy. It is 1.3817, 0.6908, 0.3454, 0.1727 and 0.0864 min respectively. Since the individual beam's dose rate is 400 cGy/min, when 2, 4, 8, 16 or 32 simultaneous beams are used, the individual beam's MU set up is 400×1.3817=553, 400×0.6908=276, 400×0.3454=138, 400×0.1727=69 or 400×0.0864=35. It is the same as in method of MU calculation for two beams.
For parallel opposed photon beam treatment method, the maximum dose to the normal tissue, Dmax is approximately D0×45% of the D0 dose from the opposite beam. When 800 cGy tumor dose is delivered at the isocenter, the MU setup when the treatment is rendered with 2, 4, 8, 16, and 32 simultaneous beams are 553, 276, 138, 69 and 35. Hence, the Dmax dose for 2, 4, 8, 16 and 32 simultaneous beams are 553+249=802, 276+124=400, 138+62=200, 69+31=100, and 35+16=51 cGy. Thus by increasing the number of simultaneous beams, the dose to the normal tissue D. is decreased.
Radiation Therapy of “Radioresistant” and Recurrent Tumors with Low Dose to Normal Tissue
Radiation therapy and radiosurgery with low maximum dose to normal tissue is better tolerated. It causes much less damage to normal tissue, the most limiting factor in radiation therapy. As the number of simultaneous beams is increased the dose to normal tissue is decreased. When the radiosurgical tumor dose is 800 cGy and the number of simultaneous beams is 8, 16 or 32 then the maximum dose to normal tissue are 200, 100 or 51 cGy. It includes the 45% dose contribution from the exiting opposing beam. Such lower dose to normal tissue is better tolerated. It facilitates radiosurgery of tumors that are very close to critical organs. In this instance, higher tumor dose is delivered by the method of simultaneous multiple beams radiation therapy while keeping the dose to normal tissue low. Because of the normal tissue intolerance to very high dose radiation, the “radio-resistant” tumors are generally treated with insufficient total tumor dose. Hence the so called “radioresistant” tumors like the melanoma are treated with lower non-curate total dose. The method of all filed simultaneous radiation to a tumor with lower dose to normal tissue and higher curative dose to tumor helps to overcome the “radioresistance” of tumors like melanoma.
Because of the lower tolerance of radiation by the normal tissue when a recurrent tumor is treated, the re-treatment of a tumor by radiation causes more complications. Because of the previous radiation, the normal tissue tolerance to radiation is low. Hence the recurrent tumors that had initial radiation therapy cannot tolerate repeat second, third or even higher retreatments. On the other hand, radiation therapy with lower dose to normal tissue by the method of all field simultaneous radiation is tolerated by the normal tissue. Hence this method of radiation therapy with multiple simultaneous beams offers the opportunity to treat recurrent and “radioresistant” tumors by radiosurgery more effectively. By this method of multiple simultaneous beams radiation therapy, the recurrent tumors that had initial radiation can be retreated for a second, third or even higher times. It opens an entirely new avenue for treating recurrent and “radioresistant” tumors that were thought as impossible before.
The same method of treating tumors by low maximum dose to normal tissue is applicable when a tumor is treated by daily fractionated radiation. If the number of simultaneous beams is 2, 4, 8, 16 or 32 and each beam's D0 dose rate 400 cGy, then the total additive dose rates, D0-T are 800, 1,600, 3,200, 6,400 and 12,800 cGy. These 2, 4, 8, 16 or 32 simultaneous beams' total additive dose rate Diso-T (biological dose rates) is 579, 1,158, 2,316, 4,632 and 9,264 cGy/min. As shown before, then the beam on time to deliver the conventional daily fractionated tumor dose of 180 cGy at the isocenter with 2, 4, 8, 16 or 32 simultaneous beams is 180/579, 1,158, 2,316, 4,632 or 9,264 cGy. It is 0.3109, 0.1554, 0.0777, 0.0389 and 0.0195 min respectively. Since the individual beam's dose rate is 400 cGy/min, when 2, 4, 8, 16 or 32 simultaneous beams are used, the individual beam's MU set up is 400×0.3109=124, 400×0.1554=62, 400×0.0777=31, 400×0.0389=16 and 400×0.0195=8. Such low maximum dose to normal tissue is readily tolerated. It also makes higher total dose radiation therapy of tumors like melanoma that needs very high dose to cure and re-treatment of recurrent tumors that were previously treated by radiation more tolerable to normal tissue; the toxicity to normal tissue from such radiation is much reduced or even eliminated. Hence this method of treatment with multiple simultaneous beams offers the opportunity to treat “radioresistant” and recurrent tumors with radiation very effectively. It opens an entirely new avenue for control and or cure of “radioresistant” and recurrent tumors.
Comparison of All Field Simultaneous Radiation Therapy with Brachytherapy
The dose rate and LET are the major factors that determine the radiobiological effectiveness (RBE). The multiple simultaneous beams additive dose rate has some similarity with brachytherapy with multiple radioactive sources. Higher the number of radioactive sources used, higher the brachytherapy's additive dose rate. Hence, for brachytherapy dose calculations, the number of radioactive sources used determines its dose rate and the total dose needed to treat a tumor. For example, in brachytherapy the total dose at dose rate of 0.357 Gy/h (35.7 cGy/h) for 7 days is 6,000 cGy. Its equivalent dose at the dose rate of 0.64 Gy/h (64 cGy/h) for 7 days is 4,600 cGy. Likewise, in AFSRT, the dose rate is a function of the number of simultaneous beams and its additive super high dose rate which is designated as super high biological dose rate. This very high biological dose rate contributes the much improved radiobiological end results. Brachytherapy cannot achieve super high dose rate like the dose rate of multiple simultaneous external beams from linear accelerators. Even a single external beam from a medical accelerator has several hundred times more dose rate per minutes than the combined cGy/h dose rate of high dose rate (HDR) brachytherapy. The clinically useful super high dose rate of multiple simultaneous external beams cannot be reached by high dose rate brachytherapy or by the combined dose rate of Gamma Knife with several small 60Co sources. Hence the isocentric super high dose rate external photon beam radiation therapy cannot be compared with HDR brachytherapy or radiosurgery with Gamma Knife with an average dose rate of 145 cGy/min. Depending on the number of beams and individual beam's machine dose rate, its biological dose rate at isocenter varies. For a 10×10-cm field size, 10-cm depth, 100-cm isocenter distance, and machine dose rate of 400 cGy/min, the isocentric additive biological dose rates for 2, 4, 6, 8, 16 or 32 simultaneous beams of the AFSRT system is 579, 1,158, 1,737,2,316, 4,632 and 9,274 cGy/min respectively.
All Field Simultaneous Radiation Therapy and Intensity Modulated Conformal Radiation Therapy
The AFSRT's multiple simultaneous high-energy photon and electron beam accelerators helps to produce conformal intensity modulated treatment as a single session treatment with simultaneous multiple beams that covers the entire treatment volume. Each of the isocentric simultaneous beam's intensity is modulated to suite the three-dimensional volume of the target. Such conformal intensity modulated simultaneous treatment of a target tumor as in the AFSRT is not feasible with the Gamma Knife or with the conventional single beam accelerator based radiosurgery. The radiobiological effectiveness of this new method of conformal treatment of a target volume with accelerator based simultaneous multiple beams with higher energy, higher dose rate and LET is much superior to that of radiosurgery with Gamma Knife or conventional linear accelerator based radiosurgery.
The linear energy transfer (LET) Concept in All Field Simultaneous Radiation Therapy
The linear energy transfer (LET) values vary for different sources of high-energy radiation beams. The LET is subdivided into track average and energy average. In track average, the amount of energy deposited in equal lengths is averaged. In energy average, the length of the track that contains equal amount of energy is calculated. (28). For x-rays, both energy average and track average are similar. Both the track average and energy average for Cobalt-60 is 0.2 KeV/μ. Likewise, the track average and energy average for 250-kV x-rays is 2.0 KeV/μ, ten times higher than that for Co-60. Because of the lower LET of Cobalt-60 with 0.2 KeV/μ has about 10% less relative biological effectiveness (RBE) than that for 250 kV x-rays.
Unlike the x-ray beams, the proton beam's LET varies with energy. The 10 MeV proton has 4.7 KeV/μ energy averages while the energy average of 150 MeV proton is like that of 60Co, only 0.5 KeV/μ. Like the x-rays, both the energy and track average for proton is the same. Hence 150 MeV protons are less effective in cell kill than 250 kV x-rays. For neutrons the track and energy average vary. The 14 MeV neutron's track average is 12 KeV/μ but its energy average is 100 KeV/μ. Because of this very high-energy average, neutron is much more effective in cell kill.
A single 250-kV x-ray beam with 2.0 KeV/μ LET deposits its energy of 2.0 KeV/μ. when it passes through the radiating tissue. Let us say that this 250-kV x-ray source is placed at 0-degree. When it is used to radiate the tissue, it's beam deposits 2.0 KeV/μ to the tissue. If a second similar x-ray source is placed at the opposite side say at 180-degree as parallel opposed to the first source and when the x-ray beams from both sources are allowed to passes through the same tissue simultaneously as parallel opposed beams, then the converging beam's energy deposited in the target tissue could double. Now the total energy deposited in the target tissue could increase from 2 KeV/μ to 4.0 KeV/μ. If similar two simultaneous 250 KeV x-ray beams are made to strike the target tissue namely one from 90 degree and another from 270-degrees as another set of simultaneous parallel opposed beams, then all four simultaneous beam's converging total additive LET could be 8 KeV/μ. These simultaneous beams improve the radiation quality and hence it's RBE. If the number of simultaneous beams were increased from four to eight, or sixteen, then the converging additive energy deposited in tissue would increase to 16 KeV/μ and 32 KeV/μ respectively. Hence its RBE also increases. RBE depends on a number of factors, namely radiation quality LET, dose rate, dose, number of fractions, and the biological endpoint.
The additive LET of simultaneous beams improves the radiation quality significantly. The LET of about 100 million-dollar costing a 150 and or higher MeV proton machine is just 0.5.0 KeV/μ, 16 times less than the additive LET as compared above. A radiation therapy machine with such high-energy simultaneous beams combined with radiation sensitizing single session hyperthermia renders a very effective radiation therapy system.
All Field Simultaneous Radiation Therapy and its Interaction with Heat, and Chemotherapy
Heat is a radiation sensitizer. Other actions of heat include enhancement of apotosis, induction of mitotic arrest or causing non-apototic cells to dye by necrosis. In fractionated hyperthermia, thermotolerance appears. It is due to synthesis of heat-shock proteins. Single fraction hyperthermia eliminates the thermotolerance. Hence single fraction radiation therapy combined with radiation sensitizing single fraction hyperthermia enhances the cytotoxicity of both radiation and hyperthermia.
Many textbooks and scientific articles describe the synergic effects of hyperthermia, and radiation with or without chemotherapy. It is summarized in chapter 28, Erick J. Hall's textbook of Radiobiology for the Radiologist (4-1, 4-2, 4-3).
They render independent but additive cytotoxicity. Hyperthermia and radiation therapy has different mechanism for cell killing; energy deposited from heat is thousand times greater than the energy deposited by radiation.
Hyperthermia is effective at S-phase of the cell cycle, a cell cycle phase at which the photon radiation is mostly ineffective to cell kill. It is also effective to cells that are nutritionally deficient and hypoxic and to cells with high PH. Radiation is effective at G2 and M phase of the cell cycle. It is less effective to cells that are in G1 and S-phase. After hyperthermia, the cell death is by apoptosis. These qualities of hyperthermia eliminate the need for reoxygenation and the cell being in a cell cycle phase that is sensitive to photon radiation. It facilitates single fraction super high dose rate photon radiation combined with hyperthermia more effective to treat a tumor. In this instance, there is no need for tumor cells being in a radiation sensitive synchrony for combined radiation and hyperthermia to be more effective. It facilitates single fraction super high dose rate radiation therapy more effectively. The sublethal damage repair after hyperthermia can take up to 120 to 160 hours. After the first treatment by hyperthermia, thermotolerance develops. Before the presence of thermotolerance, namely the very first hyperthermia treatment kills more cells than when it is repeated. Hence the first hyperthermia combined with photon radiation has a steeper cell survival curve than their combined subsequent fractionated treatments.
Heat inhibits repair of single strand breaks and chromosome aberrations induced by radiation. It is due to its ability to inhibit the sublethal damage and potentially lethal damage repair. Repair of sublethal damage does not occur if hyperthermia is applied during radiation. The super high dose rate radiation by the method of all field simultaneous radiation also inhibits the lethal and sublethal damage repair. This combined lethal and sublethal damage repair inhibition by super high dose rate radiation and hyperthermia renders photon radiation therapy's cell kill similar to that of high LET radiation. Such combined photon rotation therapy is especially very effective to treat any tumor that is resistant to photon beam radiation, like melanoma, glioblastoma, sarcoma and the like.
Diagnostic Bremsstrahlung X-Ray and Radiation Carcinogenesis
It is known that there is an increased risk of developing cancer from radiation exposure. The very early pioneers in radiation research, Marie Curie and her daughter Irene were thought to have died of leukemia (18). The long term effects of radiation induced cancers includes skin cancer, lung cancer, bone cancer, liver tumors, leukemia, thyroid cancer, breast cancer etc (18). An increased risk of cancer has occurred among longterm survivors of Hiroshima and Nagasaki atomic bombs. On the average, they received 10 to 100 millisieverts (mSv) of radiation exposure (cited in 19) which is equivalent to radiation exposure from 1 CT scan (cited in 19). Patients may receive multiple CT scans over their lifetime (cited in 19). Life time risk from radiation dose from a routine CT scan of the abdomen and pelvis of a young person with polychromatic bremsstrahlung x-ray is very high (19). In a graphic presentation it is shown to be 100% (19). Likewise, it is reported that there is an estimated risk of 1 in 270 women and 1 in 600 men who had CT coronary angiography at age 40 years will develop cancer due to radiation from the CT scan. It is about twice for 20-year-old patients and about 50% lower for 60-year old patients (19). Imaging with monochromatic x-ray renders 100-1000 times superior image quality with much less radiation to the target tissue (2) and thereby minimizing and or elimination high incidence of radiation carcinogenesis from diagnostic radiology.
Advantages of Radiological Imaging with Monochromatic X-Rays
In U.S. Pat. No. 6,687,333, “System and Method for Producing Pulsed Monochromatic X-Rays” by Carroll F. E et al, (2) and in U.S. Pat. No. 7,391,850, Compact, High-Flux, Short Pulse x-ray Source by Kaertner F. X. et al, (3) a number of superior clinical advantages of imaging with monochromatic high-flux short-pulse x-ray beam are described. However, they do not describe a beam storage ring 128 systems from which multiple simultaneous x-ray beams are switched off towards a target that is treated or imaged.
In this invention, each x-ray beam is made to diverge from its focal point towards the target that is imaged. The x-ray beam is attenuated by the tissue through which it passes through. This attenuated beam is well collimated by the arced collimator 110. This attenuated beam is collected by the stationary detectors as shown in FIG. 7 and FIG. 8. Carroll et al describes a method of generating multiple x-ray beams from a single pulse with x-ray beam reflectors such as a deflected beam is copied several times. It is not like the multiple simultaneous x-ray beams with defined focal points as in this invention; in this instance, each of the simultaneous x-ray beams is generated from a segment of the circulating x-ray beam switched off from the beam switching ring 128. Such small sequentially switched stationary x-ray beams with well defined focal point and its attenuated beam after its passage through the tissue is collected in well collimated stationary detectors 114. It improves the image quality significantly. Improving the image quality with multiple well defined and collimated beams for bremsstrahlung x-rays is described in U.S. Pat. No. 7,366,279 by Edi M. P et al (14).
Iodinated Steroids and Iodine k, l, m, n Shell Characteristic Photon and Auger Electron for Imaging and Radiation Therapy
The ability to tune the monochromatic high-flux short-pulse x-rays to the binding energy of the K shell is used to detect various elements in the body. Elements that have great affinity binding to tissue thus can be used such K-shell electron radiation for radiation therapy and imaging. A number of steroid molecules could be directly iodinated (15). It includes estrogen, testosterone, cortisone and a number of other steroids (15). Hence, iodinated estrogen and testosterone (15) could be used for tumor specific K-shell characteristic photon and electron radiation therapy and imaging.
Tumor Specific K-Shell Electron Radiation Therapy and Imaging of Estrogen Receptor Positive and Negative Breast and Testosterone Receptor Positive and Negative Prostate Cancer
In the U.S. Pat. No. 4,321,208, “Preparation of Directly Iodinated Steroid Hormones and Related Compounds” by this inventor Velayudhan Sahadevan described the directly iodinated estrogen binding to both estrogen receptor of the tumor tissue and to estrogen antiserum (15). There is estrogen receptor positive and negative breast cancer. Likewise, there is androgen receptor positive and negative prostate cancer. Estrogen binds to estrogen receptor in the breast cancer. Testosterone binds to testosterone receptor in prostate cancer.
Both estrogen receptor positive and negative tumors contain estrogen. While developing the estrogen receptor testing on breast tumors in the mid seventeen as a test for elective treatment of patients with breast cancer, this inventor also tested estrogen contents of both estrogen receptor positive and negative tumors (25). The estrogen receptor assay in tumor cytosol was performed by sucrose gradient ultracentrifugation. Tumor cytosol was prepared from the ground tumor specimen. The estrogen content in such cytosol was determined by radioimmunoassay. Both the estrogen positive and negative tumors were found to have measurable amount of estrogen. From this study, it is evident that both estrogen receptor positive and negative tumors bind to estrogen. However estrogen receptor negative tumors may not have the ability to transport estrogen into the cell interior hence its poor metabolic utilization. However, many estrogen receptor negative tumors could transform into estrogen receptor positive tumors (20).
Like the estrogen receptor positive and negative breast cancer, testosterone receptor positive prostate cancer binds to testosterone. Hence testosterone-androgen ablation is one of the major treatment modality for prostate cancer. Like the transformation of the estrogen receptor negative tumor into estrogen receptor positive tumor (20), testosterone receptor negative tumor might transform into androgen receptor positive tumor. Prostate cancer also contains estrogen receptor. Hence treatment of prostate cancer with diethyl stilbesterol (DES), an estrogenic compound or estrogen itself was a common practice in the past.
Directly iodinated estrogen and androgen offers a unique method of iodinated estrogen enhanced, tissue specific, radiation therapy by excitation of iodine bound to estrogen which binds to estrogen receptor positive breast and prostate cancer. Other iodinated steroid molecules like iodinated testosterone bound to testosterone receptor positive prostate cancer offers similar tissue specific receptor bound iodine for iodine's K-shell excitation characteristic photon and Auger resonant electron radiation therapy. Iodinated cortisone (15) is another such example. The iodinated steroid molecule is administrated either intravenously or it is implanted into the tumor as adsorbed on to charcoal nano particle dust. Such implanting of the nano particle charcoal bound iodinated steroid molecule has the advantage of inhibiting the metabolic dissociation of iodine from the steroid and thus preventing dissemination of iodine from the implant site in the tumor.
Like the naturally occurring estrogen, the iodinated estrogen also binds to estrogen receptor competitively with estrogen DES and other estrogen receptor binding anti-estrogen like molecules like tamoxifen citrate. Hence in estrogen receptor positive tumors, the iodinated estrogen will overcome the cell membrane blocks and move into the cell while in estrogen receptor negative tumors, it will be blocked at cell membrane level. Still both estrogen receptor positive and negative tumors will contain iodinated estrogen. In estrogen receptor positive tumors, first it binds to cell membrane. The cell membrane bound iodinated estrogen-estrogen receptor is then transported into the cell. In estrogen receptor negative tumors, it is mostly bound to cell membrane and might not be transported into the cell. Synergistic activation of functional estrogen receptor (ER)-α by DNA methyltransferase and histone deacetylase inhibition in human ER-α-negative breast cancer cells renders a substantial percentage of them as estrogen receptor positive cells (20). Thus the blockage of estrogen transport into estrogen negative tumor cell can be overcome. It facilitates tumor specific K-shell characteristic photon and Auger electron radiation therapy and imaging of estrogen receptor negative tumors as well. The same is applicable to estrogen receptor positive and negative prostate cancer. They are just examples of tumor specific K-shell characteristic photon and Auger electron radiation therapy and imaging. High affinity iodinated cortisone binding tumors are treated similarly with k, l, m, n shell characteristic photon and Auger electron. There are many tumors with high affinity binding to nano particle elements. Such tissue specific high affinity binding to nano particle elements are used for K-shell electron radiation therapy and imaging.
Whole Body Screening for Concealed Objects by Computerized Tomography with Multiple Simultaneous Monochromatic X-Ray and Spent Electron Beams
Whole body Computerized Tomography and Radiology with monochromatic high-flux short-pulse x-ray for screening improves the image quality 100 to 1000 times more than imaging with bremsstrahlung radiation. It has many applications including the medical and other applications like screening of a container for its contents and screening of passengers at an airport and the like. A single exposure whole body radiology and CT imaging with multiple simultaneous beams of varying energy can detect items like explosives worn under the cloths with greater efficiency and image quality. The differential pixel analysis of such a class of elements detects the suspect elements and their images. The inverse Compton scattering interaction of electron beams of varying energies with multiple laser beams of varying energies facilitates multiple simultaneous monochromatic beams of varying energies. Exposures of the whole body with such multiple simultaneous beams detect the body parts and the clothing in minor details. Likewise exposure of a container with such multiple simultaneous monochromatic beams detects the contents of a container in minor details. Differential pixel analysis of such exposures with varying energy monochromatic x-rays detects elements of different atomic structure by their differential Auger transformation radiation and their spectrums. In a container analysis, the specific atomic spectrums of Auger transformation radiation of high and low atomic weight substances and its comparison with known Auger emission of high and low atomic weight elements detects suspect elements like uranium or elements used as explosives. It detects the minor details of the fabrics and its composition as well as if it were equipped with instruments for destructive purposes including for explosive purposes. This facilitates split seconds screening of passengers at a busy airport with much higher precision than imaging with a single energy single beam exposure with monochromatic x-ray or with bremsstrahlung x-ray. It is much superior to imaging with varying energy bremsstrahlung x-ray and its spectral pixel analysis (27). Simultaneous monochromatic beams of varying energies and their very high quality imaging facilitate imaging with greater clarity. It also facilitates detection of minor fractures and defects in equipments and instruments made with precision engineering by such high quality imaging and differential pixel analysis of such exposures with tuned monochromatic x-rays of varying energies. Its use thus expands to a wide arena of innovative radiology, both in biomedical applications and in industrial radiology.